JP3739678B2 - One-pot synthesis of 2-oxazolidinone derivatives - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to an improved process for preparing substituted indole derivatives useful for the treatment and prevention of migraine. More particularly, the present invention is a 5HT _1- like receptor agonist (S) -4-{[3- [2- (dimethylamino) ethyl] -1H, which is known to be effective in treating migraine. An improved process for the preparation of -indol-5-yl] methyl} -2-oxazolidinone is provided.
[0002]
[Prior art]
Selective 5-HT _1- like receptor agonists are known as useful therapeutic agents. This 5-HT _1- like receptor mediates vascular stenosis and thereby alters blood flow in the coronary vascular bed. European Patent Specification 01339797 describes certain 5-hydroxy compounds useful for the treatment or prevention of conditions in which vascular stenosis is suggested in the coronary vascular bed (eg migraine, a condition associated with excessive dilation of the coronary vasculature). The class of HT _1- like receptor agonists is described.
[0003]
International patent specification WO 91/18897 describes a further class of compounds with very good “5-HT _1- like” receptor agonism and with excellent absorption after oral administration. Because of these properties, the compounds disclosed in WO 91/18897 make certain medical uses, especially migraine, cluster headache and headache associated with vascular disorders (hereinafter collectively referred to as “migraine”). ) Is particularly useful for prevention and treatment. One particularly preferred compound described in WO 91/18897 is (S) -N, N-dimethyl-2- [5- (2-oxo-1,3-oxazolidine-4-yl-methyl) -1H-indole- 3-yl] ethylamine (also known as (S) -4-{[3- [2- (dimethylamino) ethyl] -1 H -indol-5-yl] methyl} -2-oxazolidinone) Can be represented by formula (I):
[0004]
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Compounds of formula (I) may exist as enantiomers of (S) or (R) and are specifically exemplified in WO 91/18897. A number of possible routes for preparing the compounds of formula (I) are suggested in WO 91/18897.
[0005]
[Problems to be solved by the invention]
A new process has been discovered for preparing compounds of formula (I). This process, compared to the process disclosed in WO 91/18897, can produce the final product in high yield and large-scale pure form by using a one-pot procedure, thus intermediate time-consuming and costly It has the advantage of avoiding the need for body isolation. This new process also avoids the need for hazardous reagents such as phosgene and environmentally hazardous reagents such as tin chloride.
[0006]
[Means for Solving the Problems]
Thus, according to the first aspect of the present invention, a process for the preparation of (S) -4-{[3- [2 (dimethylamino) ethyl] -1 H -indol-5-yl] methyl} -2-oxazolidinone This process includes the following steps:
a) Carbamate is formed from methyl 4-nitro- (L) -phenylalaninate hydrochloride represented by the formula (II) by adding sodium carbonate or sodium bicarbonate and n-butyl chloroformate to react. ,
[0007]
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Step of obtaining methyl (S) -N -butoxycarbonyl-4-nitrophenylalaninate represented by the formula (III)
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b) reducing the compound of formula (III) to obtain methyl (S) -N -butoxycarbonyl-4-aminophenylalaninate represented by formula (IV)
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c) reducing the methyl ester group —CO ₂ CH ₃ in the compound of formula (IV) to obtain (S) —N-butoxycarbonyl-4-aminophenylalaninol represented by formula (V): 0010
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d) Step of ring-closing the compound of formula (V) to obtain (S) -4- (4-aminobenzyl) -2-oxazolidinone represented by formula (VI)
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e) A diazonium salt of a compound of formula (VI) is prepared and subsequently reduced to obtain hydrazine (S) -4- (4-hydrazinobenzyl) -2-oxazolidinone hydrochloride represented by formula (VII) Process [0012]
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f) A step of obtaining a compound of formula (I) by a Fischer reaction of a compound of formula (VII).
[0013]
Suitably, one or more steps a) to f) are performed using a one-pot procedure. Preferably, steps a) to d) are carried out by a one-pot procedure, followed by isolation of the compound of formula (VI) and then steps e) and f) by a second one-pot procedure.
[0014]
DETAILED DESCRIPTION OF THE INVENTION
Step a) is conveniently carried out in the presence of a solvent (eg aqueous ethyl acetate or dioxane). Aqueous ethyl acetate is preferred. Sodium carbonate rather than sodium bicarbonate is used and is preferably added prior to n-butyl chloroformate. This reaction is conveniently carried out at a non-extreme temperature, suitably in the range of 5-60 ° C. Preferably this reaction is carried out at 15-35 ° C. In a particularly preferred embodiment, the addition of sodium carbonate occurs at a temperature of about 20 ° C. and the addition of N-butyl chloroformate occurs at a temperature of about 30 ° C.
[0015]
Reduction step b) is conveniently carried out in the presence of an organic solvent (eg ethyl acetate or ethanol). Preferably step b) is performed using an ethyl acetate solution of the compound of formula (III) obtained from step a) by a one-pot procedure. Suitably step b) is preferably carried out by hydrogenation in the presence of a catalyst such as palladium charcoal. The reaction can be carried out using nitrogen at standard pressure and room temperature under a nitrogen atmosphere. The hydrogenation is preferably performed at about 20 psi of hydrogen and at an elevated temperature (eg, 30-50 ° C.). The resulting ethyl acetate solution of the compound of formula (IV) is preferably converted into a butanol solution that can be used directly as part of the one-pot procedure in step c). This conversion can be conveniently carried out by partial distillation of the ethyl acetate solution followed by butanol and rectification to remove the ethyl acetate.
[0016]
The reduction of the methyl ester in step c) is conveniently carried out in the presence of a solvent such as SVM or n-butanol. Preferably step c) is carried out by preparing an n-butanol solution from an ethyl acetate solution of the compound of formula (IV) as part of a one-pot procedure and then directly reducing the n-butanol solution. This reduction is preferably performed using sodium borohydride and conveniently carried out at non-extreme temperatures (suitably 20-40 ° C.). Preferably, this reduction is carried out in two stages; the first stage is carried out at a temperature of about 25 ° C. under nitrogen; and the second stage is carried out at about 30 ° C. The resulting n-butanol solution of the compound of formula (V) can then be dried using hydrochloric acid and ammonia. This dry n-butanol solution can be used directly in step d) as part of a one-pot procedure.
[0017]
Step d) is preferably carried out with a dry solution of the compound of formula (V) (eg a dry butanol solution). Such a dry butanol solution is advantageously prepared by drying the n-butanol solution produced by step c). This dry n-butanol solution is preferably decolorized using charcoal before carrying out the ring closure reaction. This ring closure may conveniently be performed using sodium methoxide in an alcohol solvent (eg methanol). Most preferably, ring closure is performed using a 30% methanol solution of sodium methoxide. This reaction is preferably carried out at elevated temperatures (suitably in the range of 50 to 120 ° C.). Preferably, this reaction is carried out at about 85 ° C. The resulting compound of formula (VI) can then be isolated. This isolation can be performed by standard centrifugation, filtration and drying methods.
[0018]
Step e) is preferably carried out on the isolated compound of formula (VI). Isolation can be accomplished, for example, by well-known centrifugation, filtration and drying techniques. Diazonium salt formation can be performed at low temperature using an aqueous sodium nitrite solution, preferably in the presence of concentrated hydrochloric acid. Preferably, this salt formation is carried out at a low temperature (eg 0-5 ° C.). Hydrazine formation is then carried out with a diazonium salt solution by using sodium sulfite as a reducing agent. Sodium sulfite is suitably in the form of an aqueous solution. This reduction is advantageously carried out in two stages: the first stage is the addition of sodium sulfite; the second stage is the addition of hydrochloric acid. Preferably the first stage is carried out at a temperature below 10 ° C. Preferably the second stage is carried out at an elevated temperature (eg 55-60 ° C.).
[0019]
The solution of the compound of formula (VII) obtained from step e) is preferably used directly in step f) as a one-pot procedure. Step f) is a Fischer reaction. It has been found advantageous to carry out this reaction at a relatively high dilution in order to maximize the purity of the final product. Accordingly, the solution obtained from step e) is preferably diluted with water. The Fischer reaction is then carried out by adding 4,4-diethoxy- N , N -dimethylbutylamine, suitably under a nitrogen atmosphere. Preferably, when 4,4-diethoxy- N , N -dimethylbutylamine is added, the dilute solution is hot. A suitable temperature is in the range of 75-105 ° C and preferably about 90 ° C. This reaction preferably proceeds under reflux.
[0020]
After the reaction is complete, the compound of formula (I) can be extracted using standard techniques. Suitably the refluxed reaction product is cooled and adjusted to about pH 7 using, for example, sodium hydroxide. The pH adjusted product can then be extracted with ethyl acetate and the aqueous layer adjusted to about pH 10 with sodium hydroxide. The product can then be extracted at about 50 ° C., followed by standard decolorization, filtration, distillation, centrifugation and drying techniques.
[0021]
A particularly preferred reaction scheme for preparing compounds of formula (I) is as follows:
[0022]
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[0023]
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According to a second aspect of the present invention, there is provided a purification process for (S) -4-{[3- (dimethylamino) ethyl] -1 H -indol-5-yl] -methyl} -2-oxazolidinone, The process includes the following steps:
a) Dissolve crude (S) -4-{[3- (dimethylamino) ethyl] -1 H -indol-5-yl] -methyl} -2-oxazolidinone in a refluxing mixture of ethanol in ethyl acetate And filtering the hot solution;
b) slowly cooling the filtered solution to a temperature of about 5 ° C;
c) centrifuging the product from step b), washing with ethyl acetate and then drying; and d) treating with acetone to remove the solvated ethyl acetate.
[0024]
Preferably, the refluxing mixture is 10% ethanol in ethyl acetate. The hot solution is suitably decolorized using decolorizing charcoal prior to filtration using a filter aid.
[0025]
The cooled and filtered solution of step b) is suitably agitated for a long time (preferably about 18 hours) before centrifugation.
[0026]
The drying step of step c) is preferably carried out under vacuum. Suitably the product is dried at a temperature that is not extremely high (eg 40-60 ° C, preferably about 50 ° C).
[0027]
The dried solid product of step c) is conveniently treated with a 20% acetone mixture in water at a non-extreme temperature (preferably 15-30 ° C., eg room temperature). The resulting suspension is then cooled to a non-extremely low temperature (preferably about 5 ° C.) and stirred. The product is then centrifuged, washed with ethyl acetate and dried preferably at a temperature of about 45 ° C. under vacuum.
[0028]
The resulting product is a high purity unsolvated solid.
[0029]
In a third aspect, the present invention provides unsolvated pure (S) -4-{[3- (dimethylaminoethyl) -1 H -indol-5-yl] -methyl} -2-oxazolidinone. provide. In a further aspect, the present invention provides compounds of formula (III), (IV), (V) and (VI) as defined herein above.
[0030]
In yet a further aspect, the present invention provides a process for preparing compounds of formula (III), (IV), (V) and (VI) as follows.
[0031]
Compound (III): Process step a) of the first aspect of the invention and preferably the process described on page 4;
Compound (IV): Process according to the process step b) of the first aspect of the invention and preferably the paragraph spanning pages 4, 5;
Compound (V): Process step c) of the first aspect of the invention and preferably the process described on page 5; and Compound (VI): Process step d) of the first aspect of the invention and preferably page 5 The process described in
[0032]
The invention is further described by the following examples.
[0033]
【Example】
Example 1
(S) -4- [2- (dimethylamino) ethyl] -1 H - indol-5-yl] methyl} process stage for preparing 2-oxazolidinone large amounts 1: Methyl 4-nitro - (L) - phenyl Preparation reaction of phenylaninate hydrochloride
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A solution of hydrogen chloride in methanol is prepared by passing hydrogen chloride gas through a reactor containing methanol while maintaining the procedure temperature below 25 ° C. The reactor is charged with 4-nitro- ( L ) -phenylalanine and refluxed for about 1 hour. Cool to about 0 ° C. and centrifuge the product (methyl 4-nitro- ( L ) -phenylalaninate hydrochloride). The product is washed with methanol and dried in vacuo at 50 ° C.
[0035]
Stage 2: Preparation reaction of methyl (S) -N-butoxycarbonyl-4-nitrophenylalaninate
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Procedure Charge the reactor with demineralized water, methyl 4-nitro- ( L ) -phenylalaninate hydrochloride, sodium carbonate and ethyl acetate and cool the reactor contents to about 20 ° C. with stirring. Add n-butyl chloroformate to the reaction mixture while maintaining the temperature at about 30 ° C. and stir for about 30 minutes. Separate the aqueous layer and wash the ethyl acetate solution with water. The methyl ( S ) -N -butoxycarbonyl-4-nitrophenylalaninate solution in ethyl acetate is used directly in the next stage.
[0037]
Stage 3: Preparation reaction of methyl (S) -N-butoxycarbonyl-4-aminophenylalaninate
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Procedure A reactor was charged with a 5% palladium charcoal catalyst, methyl ( S ) -N butoxycarbonyl-4-nitrophenylalaninate in ethyl acetate and maintained at a temperature between 30 ° C. and 50 ° C. with about 20 psi of hydrogen. Hydrogenate. Upon completion, the catalyst is filtered off through a filter aid and washed with ethyl acetate. Wash the ethyl acetate solution with aqueous sodium carbonate solution. The ethyl acetate solution of methyl ( S ) -N -butoxycarbonyl-4-aminophenylalaninate is partially distilled, butanol is added and the mixture is rectified to remove the ethyl acetate. This butanol solution is used directly in the next stage.
[0039]
Stage 4: Preparation reaction of (S) -N-butoxycarbonyl-4-aminophenylalaninol
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Procedure The reactor is charged with a butanol solution of methyl ( S ) -N -butoxycarbonyl-4-aminophenylalaninate from stage 3 and diluted to the desired volume with n-butanol. Cool the reactor contents to about 25 ° C. Under a nitrogen atmosphere, half of the total amount of sodium borohydride is added while maintaining the reaction temperature at about 25 ° C. Stir for 3 hours, then add the other half of sodium borohydride. The mixture is further stirred for 5 hours and warmed to 35 ° C. After this time, the reaction mixture is stirred for about 12 hours and then aqueous hydrochloric acid is slowly added while maintaining the temperature at about 30 ° C. to decompose any excess sodium borohydride. Add water, warm to about 35 ° C. and adjust to about pH 10 by adding ammonia solution. The aqueous layer is separated and the organic layer is washed with water while maintaining the temperature at about 35 ° C. While azeotropically distilling some of the butanol, the solution is dried. This dry butanol solution is used directly in the next stage.
[0041]
Stage 5: Preparation reaction of (S) -4- (4-aminobenzyl) -2-oxazolidinone
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Procedure Charge the reactor with a dry n-butanol solution of ( S ) -N -butoxycarbonyl-4-aminophenylalaninol from stage 4 and add decolorized charcoal. The dry solution is treated at about 85 ° C. by slowly adding sodium methoxide in methanol. The reaction mixture is heated at 85 ° C. with slow addition of sodium methoxide in methanol. The reaction mixture is heated for a further 30 minutes at 85 ° C. and then hot filtered through a filter aid. After cooling the solution at 5-10 ° C. for at least 8 hours, the mixture is centrifuged and the filtered product is washed with n-butanol and dried in a vacuum at about 50 ° C.
[0043]
Stage 6A: Preparation reaction of (S) -4- {3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] methyl} -2-oxazolidinone
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[0045]
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Procedure Charge the reactor with concentrated hydrochloric acid, demineralized water and ( S ) -4- (4-aminobenzyl) -2-oxazolidinone. Cool the reactor contents to between 0-5 ° C and add aqueous sodium nitrite solution while maintaining the temperature below 5 ° C. After stirring for about 30 minutes, the diazonium salt solution is added to the cooled aqueous solution of sodium sulfite while maintaining the temperature below 10 ° C. After stirring for 15 minutes, the product mixture is slowly heated to about 55-60 ° C. and then hydrochloric acid is added slowly. The solution is maintained at about 60 ° C. for about 18 hours.
[0046]
The reaction mixture is diluted with water and heated to about 90 ° C. Under a nitrogen atmosphere, 4,4-diethoxy- N , N -dimethylbutylamine is slowly added and heated to reflux for about 3 hours. Cool and adjust the mixture to about pH 7 using sodium hydroxide solution. Extract with ethyl acetate, then adjust the aqueous layer to about pH 10 again using sodium hydroxide solution. Extract the product at about 50 ° C. using ethyl acetate. The combined ethyl acetate extracts (including product) are treated with decolorizing charcoal and filtered through a filter aid. Most of the solvent is distilled off and the suspension is cooled to about 5 ° C. The crude product is centrifuged, washed with ethyl acetate and vacuum dried at 50 ° C.
[0047]
Stage 6B: (S) -4- {3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] methyl} -2-oxazolidinone purification raw material Amount of ethyl acetate 109.4 liters of ethanol 12.3 Liter charcoal 2.4kg
Ethyl acetate (product washing) 5.0 liters acetone 11.8 liters water (desalted) 47.3 kg
Water (desalted) (product wash) 10.0 kg
Filter aid 2.0kg
The crude product of Step 6A is dissolved in a refluxing mixture of 10% ethanol in ethyl acetate, treated with decolorizing charcoal and filtered hot through a filter aid. The solution is slowly cooled to above 5 ° C. and stirred for 18 hours. The purified product is then centrifuged, washed with ethyl acetate and vacuum dried at 50 ° C. To remove the solvated ethyl acetate, add the dry solid at ambient temperature to a mixture of 20% acetone in water and stir for 1 hour. The suspension is cooled to about 5 ° C. for about 1 hour, after which the product is centrifuged, washed with ethyl acetate and dried in a vacuum at about 45 ° C.
[0048]
(Example 2)
Another Preparation of Methyl (S) -N -butoxycarbonyl-4-nitrophenylalaninate (Compound of Formula (III)) Methyl-4-nitro- (L) -phenylalaninate hydrochloride (40.00 g, .0. 153 mol) and sodium bicarbonate (73 g, 0.870 mol) in 1,4-dioxane (1000 ml) was stirred at about 10 ° C. under anhydrous conditions. A solution of butyl chloroformate (23.12 g, 21.52 ml, 0.169 mol) in 1,4-dioxane (200 ml) was added over 10 minutes (reaction temperature about 13 ° C.). The resulting suspension was warmed to room temperature and stirred for 3 hours. The reaction was slowly quenched in water (1600 ml) and then extracted with ethyl acetate (3 × 650 ml). The combined ethyl acetate extracts were washed with brine (1000 ml), dried over anhydrous magnesium sulfate, filtered and evaporated to an oil. Residual solvent was removed using an oil pump at 50 ° C. to give a syrup (51.34 g, 103% yield). This syrup solidified gradually upon standing.
[0049]
TLC [SiO ₂ , EtOAc] was homogeneous (Rf = 0.59).
[0050]
¹ H NMR (60 MHz, CDCl ₃ ) was consistent with the structure of carbamate.
[0051]
Example 3
Another Preparation of Methyl (S) -N -butoxycarbonyl-4-aminophenylalaninate (Compound of Formula (IV)) Compound [45.00 g, 0.139 mol] of ethanol (845 ml) prepared by Example 2 ) The solution was added to wet 10% palladium on carbon (type 87L, 61.1% H ₂ O) [about 4.5 g] under a nitrogen atmosphere. The reaction was set to hydrogenation at room temperature under standard pressure. Hydrogen was stably taken in over 9 hours (about 9700 ml). The catalyst was filtered off on hyflo and washed with ethanol (100 ml). The filtrate was concentrated in vacuo (water bath temperature <40 ° C.) and the last minute of solvent was removed using an oil pump to give a brown gum (41.70 g, 101%).
[0052]
TLC [SiO ₂ , EtOAc] showed the desired product (Rf = 0.49) with a minor amount of impurities that were faster running.
[0053]
¹ H NMR (300 MHz, CDCl ₃ ) was consistent with product structure and residual ethanol.
[0054]
(Example 4)
Another preparation of (S) -N-butoxycarbonyl-4-aminophenylalaninol (compound of formula (V)) Stirred sodium borohydride (14.80 g, 0.390 mol) in SVM (150 ml) To the suspension was added dropwise an SVM (460 ml) solution of the compound prepared by Example 3 [76.40 g, 0.260 mol] at room temperature. The reaction was left stirring overnight (about 18 hours), after which TLC [SiO ₂ , EtOAc] showed complete consumption of starting material. The reaction mixture was acidified to about pH 4 with 2M aqueous hydrochloric acid with ice cooling to a temperature of about 10 ° C. The product mixture was concentrated to a solid residue and saturated aqueous sodium bicarbonate (2000 ml) was added slowly. The aqueous mixture (pH about 8) was extracted with ethyl acetate (2 × 750 ml) and the combined organic extracts were dried (magnesium sulfate), filtered and concentrated to a pale pink waxy solid (64.56 g Yield 93%).
[0055]
TLC [SiO ₂ , EtOAc] showed the desired product (Rf = 0.33) with a small amount of impurities.
[0056]
¹ H NMR (60 MHz, CDCl ₃ ) was consistent with the structure of alaninol.
[0057]
【The invention's effect】
According to the present invention, the following processes, intermediates and uses are provided.
(1) A process for preparing (S) -4-{[3- [2- (dimethylamino) ethyl] -1 H -indol-5-yl] methyl} -2-oxazolidinone comprising the following steps: Inclusion process:
a) Carbamate is formed from methyl 4-nitro- (L) -phenylalaninate hydrochloride represented by the formula (II) by adding sodium carbonate or sodium bicarbonate and n-butyl chloroformate to react. ,
[0058]
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Step of obtaining methyl (S) -N -butoxycarbonyl-4-nitrophenylalaninate represented by the formula (III)
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b) reducing the compound of formula (III) to obtain methyl (S) -N -butoxycarbonyl-4-aminophenylalaninate represented by formula (IV)
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c) reducing the methyl ester group —CO ₂ CH ₃ in the compound of formula (IV) to obtain (S) —N-butoxycarbonyl-4-aminophenylalaninol represented by formula (V): 0061]
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d) Step of ring-closing the compound of formula (V) to obtain (S) -4- (4-aminobenzyl) -2-oxazolidinone represented by formula (VI)
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e) A diazonium salt of a compound of formula (VI) is prepared and subsequently reduced to obtain hydrazine (S) -4- (4-hydrazinobenzyl) -2-oxazolidinone hydrochloride represented by formula (VII) Process [0063]
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f) A step of obtaining a compound of formula (I) by a Fischer reaction of a compound of formula (VII).
(2) A process according to item 1 above, wherein one or more of steps a) to f) are performed using a one-pot procedure.
(3) Steps a) to d) carried out by a one-pot procedure, followed by isolation of the compound of formula (VI), and then steps e) and f) carried out by a second one-pot procedure. Or the process according to 2.
(4) The process according to any one of items 1 to 3, wherein step a) is carried out using sodium carbonate in the presence of an aqueous ethyl acetate solvent.
(5) The process of paragraph 4 above, wherein in step a) sodium carbonate is added at a temperature of about 20 ° C and N-butyl chloroformate is added at a temperature of about 30 ° C.
(6) The process according to any one of items 1 to 5, wherein step b) is carried out by hydrogenation.
(7) The process according to any one of Items 1 to 6, wherein the reduction in step c) is performed using sodium borohydride.
(8) The process according to any one of the above items 1 to 7, wherein step d) is carried out in a dry butanol solution of the compound of formula (V).
(9) The process according to any one of the above items 1 to 8, wherein the ring closure is carried out at a temperature in the range of 50 to 120 ° C using a 30% methanol solution of sodium methoxide.
(10) Step e) is carried out by i) reacting a compound of formula (VI) with sodium nitrite and ii) reducing the diazonium salt formed in i) using sodium sulfite Item 10. The process according to any one of Items 1 to 9.
(11) The process according to any one of the above items 1 to 10, wherein the Fischer reaction in step f) is carried out at a relatively high dilution.
(12) (S) -4 - {[3- ( dimethylamino) ethyl] -1 H - indol-5-yl] - methyl} -2-oxazolidinone a purification process, the process comprising the steps of :
a) Dissolve crude (S) -4-{[3- (dimethylamino) ethyl] -1 H -indol-5-yl] -methyl} -2-oxazolidinone in a refluxing mixture of ethanol in ethyl acetate And b) filtering the hot solution, c) slowly cooling the filtered solution to a temperature of about 5 ° C., c) centrifuging the product from step b), washing with ethyl acetate, and then drying; d) A step of treating with acetone to remove solvated ethyl acetate.
(13) pure unsolvated (S) -4 - {[3- (dimethylamino ethyl) -1 H - indol-5-yl] - methyl} -2-oxazolidinone.
(14) Intermediate of formula (III)
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(15) Intermediate of formula (IV)
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(16) Intermediate of formula (V)
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(17) Intermediate of formula (VI)
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(18) A process for preparing a compound of formula (III) comprising:
[0068]
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A process comprising reacting a compound of formula (II) with sodium carbonate and n-butyl chloroformate
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(19) A process for preparing a compound of formula (IV) comprising:
[0070]
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Process comprising the step of reducing the compound of formula (III)
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(20) A process for preparing a compound of formula (V) comprising:
[0072]
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Process comprising the step of reducing the compound of formula (IV)
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(21) A process for preparing a compound of formula (VI) comprising:
[0074]
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Process comprising the step of cyclizing the compound of formula (V)
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(22) Use of the intermediate according to item 14 in the manufacture of a composition for pharmaceutical use.
(23) Use of the intermediate according to item 15 in the manufacture of a composition for pharmaceutical use.
(24) Use of the intermediate according to item 16 above in the manufacture of a composition for pharmaceutical use.
(25) Use of the intermediate according to item 17 in the manufacture of a composition for pharmaceutical use.
(26) The use according to any one of the above items 22 to 25, wherein the composition is used in the treatment and prevention of migraine.

Claims (1)

A process for preparing a compound of formula (III) comprising:
Formula (II )
A process comprising reacting a compound of the following with sodium carbonate and then with n-butyl chloroformate.